1. Field of the Invention
This invention relates to novel polymer-drug compounds and their use in providing sustained release drug delivery to human and other warm-blooded animals. The polymer-drug compounds provide a mechanism whereby the rate of release and availability of the drug may be regulated so that the quantity of a drug which is released at a particular time or at a particular site is relatively constant and uniform over extended periods of time.
2. Description of Prior Art
Drugs are conventionally administered orally or via injection, often at a site remote from the target. Over a relatively short period of time, the drug diffuses into the circulation system of the patient and is distributed to the various organs, at least one of which is the intended target for the drug. The action of the drug on organs other than the target may result in undesirable side effects. Finally, the drug is metabolized or otherwise irreversibly removed from the organism by excretion or chemical deactivation.
When drugs are delivered orally or by injection, the level and duration of availability of the drug cannot be controlled independently; only the size and frequency of the dose can be manipulated. Typically, there is an initially high concentration of available drug at the site of injection or in the circulatory system which then decreases gradually as the drug is distributed and consumed within the body of the patient.
In controlled sustained delivery, a formulation of the drug and a carrier is administered to the patient by injection or implantation. The carrier forms a drug reservoir that protects the stored drug from extraneous removal mechanisms and releases the drug to the biological reservoir at a predetermined rate. Controlled sustained delivery of a drug prevents undesirable peaking of blood levels and makes the drug available at an optimum and uniform concentration over an extended period of time. Only the released drug is subject to removal via metabolism and excretion.
U.S. Pat. Nos. 3,773,919, 3,755,558, and 3,997,512 describe formulations of various polylactides, polyglycolides and copolymers of glycolide and lactide with some well-known drugs in order to achieve slow release of the drugs when implanted or applied topically to humans. These compositions are designed to release the drug over an extended period of time as the polymer of the mixture is slowly absorbed in the system. The polymer itself is nonreactive to body tissue and degrades into harmless products which are metabolized or excreted by the host body.
We have discovered that polymers of alkylene oxalate are also absorbed slowly in animal tissue without significant adverse tissue reaction.
Polymers of poly(alkylene oxalates) and the preparation thereof are described in the art. Carothers et al, J. Amer. Chem. Soc. 52, 3292 (1930), for example, describes the ester interchange reaction of diols such as ethylene glycol, 1,3-propanediol, or 1,4-butanediol with diethyl oxalate to yield a mixture of monomer, soluble polymer and insoluble polymer. The reaction of oxalic acid and an alkylene glycol to form polyester resins is described in U.S. Pat. No. 2,111,762, while the preparation of polyesters of fiber-forming quality from dicarboxylic acids and diols is described in U.S. Pat. No. 2,952,652. The reaction of ethylene glycol with oxalic acid to form fiber-forming polymer was described recently in J. Polym. Sci., Polym. Chem. Ed., 15, 1855 (1977). Superpolyesters of fiber-forming quality and derived from dibasic acids plus glycols are described in U.S. Pat. Nos. 2,071,250 and 2,071,251. Linear polyesters of oxalic acid have been reported as having high melting points, being soluble in many solvents, capable of forming films, and readily hydrolyzed [Savinov et al, Polym. Sci. USSR 6, 1475 (1964)].
There was, however, no appreciation in the prior art of the absorbability of poly(alkylene oxalate) polymers in animal tissue, and no suggestion for the use of poly(alkylene oxalate) polymers in surgical applications. In particular, there has been no suggestion in the art to utilize polymers of alkylene oxalates in the preparation of absorbable polymer-drug compositions in accordance with the present invention.